Deciphering the molecular machinery of translational control in Plasmodium falciparum gametocytes

• Applicant: Dr. Sandra Bennink
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 490654156

The life-cycle of the malaria parasite Plasmodium falciparum involves two hosts, the human and the mosquito. One of the major challenges during transmission from the human to the mosquito is the rapid adaptation of the parasite to the insect midgut. Responsible for establishing an infection in the mosquito are the intraerythrocytic gametocytes of P. falciparum. When entering the midgut with the blood meal, the gametocytes rapidly convert into fertile gametes to ensure fertilization and hence life-cycle progression. In order to pro-actively prepare for transmission, female gametocytes synthesize transcripts that encode proteins needed for life-cycle progression in Anopheles and store these in an inactive form in stress granules. The transcripts are bound to ribonucleoprotein particles and released from these repressors to be introduced to the translation machinery at the onset of gametogenesis. Despite the known role of eukaryotic stress granules in cell survival and differentiation, the protein and RNA compositions of stress granules in malaria parasites and their dynamics during life-cycle progression are to date not well described. Recently, our group identified a novel component of stress granules in female gametocytes, the heptahelical protein 7-Helix-1, which interacts with the stored mRNAs and a variety of known ribonucleoproteins. 7-Helix-1 is a homolog of the stress response regulator LanCL2, which in human cells interacts with components of the mTORC signaling pathway – a master controller of protein synthesis in eukaryotes. Based on our previous findings we hypothesize that 7-Helix-1 promotes the reactivation of the translational machinery at the onset of female gametogenesis via an mTORC-related pathway. In order to decipher the molecular machinery of translational control in malaria gametocytes, we here propose to 1) unveil the interactome of 7-Helix-1 via BioID-based techniques intending to reveal the protein composition of stress granules; 2) determine the stress granule transcriptome, using RIP-Seq and TRIBE methodologies; and 3) characterize putative components of the mTORC pathway of P. falciparum by reverse genetics. Insights gained by this study will not only advance our understanding of the translational regulation during malaria transmission, but may unveil novel therapeutic targets to combat this deadly infectious disease.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Gabriele Pradel